FENDING OFF BIOTERRORISM
Bay Area scientists designing ways to fight off lethal flu strains, radiation bombs by quickly modifying a human cell’s behavior
Inspired by recent breakthroughs in genetics, Bay Area scientists are dialing up our inner strength to survive a bioterrorism attack.
Two Defense Department-funded projects strive to give us a new kind of DNA superpower if a rogue actor unleashes a lethal flu virus or a radiation-laced “dirty bomb.”
Our existing tools — vaccines, medicines, even bone marrow transplants — aren’t fast or furious enough to defend us.
So the Bay Area teams — at Stanford, UC San Francisco, UC Berkeley and the San Francisco biotech firm DNARx — are using a modified form of CRISPR gene editing to boost our body’s ability to briefly and reversibly protect us from these threats. The concept: In a crisis, we’d get a quick “puff” of gene-altered medicine to the lungs, like asthma treatment.
If successful, the therapies could be given before or after exposure to reduce illness and death.
“Researchers seek to improve rates of survival and recovery in catastrophic scenarios for which reliable
countermeasures don’t currently exist,” said Renee Wegrzyn, program manager for the military’s PREPARE (Preemptive Expression of Protective Alleles and Response Elements) initiative.
The science behind the projects could have powerful peacetime application as well, helping us fend off ordinary dangers such as aggressive strains of seasonal flu and high-dose radiation cancer treatment.
The initiative is funded by the military’s “mad science” venture capital program, called DARPA, which pioneered technologies ranging from the Internet and personal computer to the laser and disaster relief robots. DNARx and the Stanford scientists were awarded up to $10.7 million. UCSF and UC Berkeley, through their collaboration called Innovative Genomics Initiative, received $10 million, with another $10 million awarded in two years.
It’s a biological version of the nation’s ballistic missile defense program, our network of interceptors, radars, sensors and weapons designed to track and destroy an incoming attack.
Experts say that if a terrorist designed and released a deadly flu virus, it would overwhelm our health care system. It happened three times in the last century — the 1918 global outbreak also known as the Spanish flu, the 1957 Asian flu and the 1968 Hong Kong flu — and those virulent strains of the virus killed millions.
A radioactive bomb also would quickly strain our resources. Now we treat victims of radiation illness with transfusions and medications. But very large doses of nuclear fallout are lethal. Additionally, resilience to radiation would also help the thousands of cancer patients in the U.S. who get therapy to shrink their tumors. It also might reduce exposure due to illness, which gives cancers a chance to regrow.
Despite the advantages, some critics fear that developing enhanced biodefenses could trigger a biological arms race with other nations.
They worry that the U.S. could leverage this biotech advantage, using it to protect soldiers in an offensive, not defensive, strategy. Or it could be used to reduce the enemy population’s immune defenses.
“Inadvertently, the project may contribute to rising international tensions in the biological field,” said Filippa Lentzos, a senior research fellow in the Departments of War Studies and of Global Health and Social Medicine at England’s King’s College London.
Instead, she urged other biodefensive measures, such as better protective masks and clothing, air and water filtration systems, detection and identification devices, and decontamination systems.
But given the ubiquity of biotechnology, DARPA says it is important to plan for weaponized pathogens.
It sounds like sci-fi. But these tools simply harness the power of our own innate defenses, written in our DNA, scientists say.
Every day, our body fends off the natural radiation of the sun. And our immune system mounts a defense when we get the flu. But these responses aren’t enough to defend us from a catastrophic onslaught.
“The human body is amazingly resilient. Every
one of our cells already contains genes that encode for some level of resistance to specific health threats, but those built-in defenses can’t always express quickly or robustly enough to be effective,” Wegrzyn said in a statement.
The project was conceived as a result of breakthroughs in the field of genetic editing, launched by discovery of the tool CRISPR-Cas9. This revolutionary technology is less than a decade old, but its use has already exploded in medical and agricultural research and is anticipated to grow into a $10 billion market in 2025.
But unlike CRISPRCas9, the goal isn’t to permanently edit our underlying genetic code. Instead, it uses a modified form of the technique to control genes’ function, changing the behavior of cells.
Rather than cutting DNA, it binds to it, and can swap in different molecular tools to dial up or down gene expression. Repressor molecules work like red lights, telling gene activity to stop. Activator molecules are like green lights, telling it to go. This influences the production of protective proteins.
The gene changes are transient, so they’d only last for a couple of weeks or months. They’re not passed on to future generations.
“Deliver the message,” said professor Jonathan Weissman of the Department of Cellular and Molecular Pharmacology at UCSF, who is working with IGI’s
Fyodor Urnov to combat radiation. “And once the messenger is gone, you’re back to normal.”
The specific strategies differ for flu and radiation exposure.
To combat flu, Stanford teams led by the San Francisco biotech company DNARx under investigator Dr. Robert Debs, aim to develop a gene therapy that prevents infection by boosting the natural immune response and other protective functions of our nasal passages and lungs.
They’re also developing a gene therapy that could kill the virus in infected cells, so it doesn’t multiply and cause an epidemic.
“Hopefully, you can protect
the cell from being infected, but if it is, you want to stop the virus from taking over the cells,” Debs said.
He is working with Stanford’s pediatric immunologist David Lewis, bioengineer Stanley Qi and research scientist Marie LaRussa.
This new approach, which could be administered as a nebulizer or inhaler, could provide near instantaneous immunity from all types of influenza viruses, and prevent epidemics.
If successful, it could also be used against the fastchanging strains of flu that race around the globe every year, and other deadly viruses in the future.
Invincibility against nuclear fallout means finding a different target. A team led by Weissman is finding genes — especially in the rapidly dividing blood and gut cells — that when turned on or off can protect against acute radiation sickness.
“We are not just keeping these cells alive,” Weissman said. “We’re keeping them alive in a way that they still have the ability to replenish.”
The researchers strive to create treatments that could be given either before or after exposure, and persist for several weeks.
It also could help astronauts survive radiation while traveling in space.
Before being tested in humans, both approaches need to be tested extensively in animals. Three other research universities, in addition to Stanford and IGI, have been awarded contracts. By the end of the project, DARPA wants the teams to submit at least one product for Food and Drug Administration approval.
It’s a futuristic bet, the scientists agree.
“But there is nothing inherent about life,” Weissman said, “that it can’t survive.”